Pathogenic HIV and SIV infections of humans and Rhesus Macaques (RMs), respectively, result in progressive CD4+ T-cell depletion and AIDS. In contrast, natural, non-progressive SIV infection of sooty mangabeys (SMs) is characterized by preservation of CD4+ T-cell counts. The mechanisms responsible for the differential ability to maintain CD4+ T-cell homeostasis in SMs versus RMs are currently unknown. Scope of this work is to elucidate the cellular and molecular basis for this divergent phenotype. In previous work, we explored the possibility that the regenerative potential of CD4+ T-cells is different between SMs and RMs and conducted experiments in which these cells were experimentally depleted with anti-CD4 monoclonal antibodies. In this study, we expand upon this work by proposing a series of in vivo comparative experiments aimed at identifying species-specific features of CD4+ T-cell homeostasis in SMs and RMs. In Aim #1, we will compare in these two species, the phenotypical, functional, and molecular proprieties of CD4+ T- cells that repopulate the pools following experimental depletion of these cells. In Aim #2, we will assess the effect of CCR5 inhibition on the kinetics of CD4+ T-cell repopulation post-depletion. This study builds on the observation that CD4+ T-cell homeostatic proliferation is associated with marked CCR5 up-regulation in RMs but not in SMs. In Aim #3, we will determine the effect of IFN-1 on the repopulation of CD4+ T-cells after depletion. This experiment builds on the observation that chronic SIV infection of RMs, which is characterized by CD4+ T-cell depletion, is associated with up-regulation of IFN-1-stimulated genes (ISGs), while chronic SIV infection of SMs, which is characterized by preservation of CD4+ T-cell homeostasis, is associated with normal levels of ISGs. The elucidation of the mechanisms regulating CD4+ T-cell homeostasis in non-human primates that are natural or non-natural hosts for SIV may provide fundamental insights in the mechanisms responsible for CD4+ T-cell depletion and progression to AIDS, and thus help the design of therapeutic intervention aimed at preserving the CD4+ T-cell compartment and, ultimately, the functionality of the immune system in HIV-infected individuals. PUBLIC HEALTH RELEVANCE: In this study we will perform a series of in vivo experiments aimed at determining whether species-specific features of CD4+ T-cell homeostasis impact differently the reconstitution of CD4+ T-cell compartment in SMs and RMs. To this aim, the molecular features of CD4+ T-cells that repopulate the depleted pools following Ab- mediated CD4-depletion, and the contribution of CCR5 and/or IFN-a in CD4+ T-cell homeostasis will be compared between SMs and RMs. This experimental approach will allow us to determine the cellular and molecular mechanisms responsible for the different ability of regulating CD4+ T-cell homeostasis in monkey species that are natural or non-natural hosts for SIV.